Melatonin is an ancient multi‐tasking molecule produced by the pineal gland and by several extrapineal tissues. A variety of activities has been ascribed to this hormone in different physiological and pathological contexts, but little is known about its role in peripheral neuroregeneration. Here, we have exploited two different types of injury to test the capability of melatonin to stimulate regeneration of motor axons: (a) the acute and reversible presynaptic degeneration induced by the spider neurotoxin α‐Latrotoxin and (b) the compression/transection of the sciatic nerve. We found that in both cases melatonin administration accelerates the process of nerve repair. This pro‐regenerative action is MT1‐mediated, and at least in part due to a sustained activation of the ERK1/2 pathway. These findings reveal a receptor‐mediated, pro‐regenerative action of melatonin in vivo that holds important clinical implications, as it posits melatonin as a safe candidate molecule for the treatment of a number of peripheral neurodegenerative conditions.

Schwann cells are key players in neuro-regeneration: They sense "alarm" signals released by degenerating nerve terminals and differentiate toward a proregenerative phenotype, with phagocytosis of nerve debris and nerve guidance. At the murine neuromuscular junction, hydrogen peroxide (HO) is a key signal of Schwann cells' activation in response to a variety of nerve injuries. Here we report that Schwann cells exposed to low doses of HO rewire the expression of several RNAs at both transcriptional and translational levels. Among the genes positively regulated at both levels, we identified an enriched cluster involved in cytoskeleton remodeling and cell migration, with the Annexin (Anxa) proteins being the most represented family. We show that both Annexin A2 (Anxa2) transcript and protein accumulate at the tips of long pseudopods that Schwann cells extend upon HO exposure. Interestingly, Schwann cells reply to this signal and to nerve injury by locally translating Anxa2 in pseudopods, and undergo an extensive cytoskeleton remodeling. Our results show that, similarly to neurons, Schwann cells take advantage of local protein synthesis to change shape and move toward damaged axonal terminals to facilitate axonal regeneration.

Envenomation by snakes is a major neglected human disease. Hospitalization and use of animal-derived antivenom are the primary therapeutic supports currently available. There is consensus that additional, not expensive, treatments that can be delivered even long after the snake bite are needed. We recently showed that the drug dubbed NUCC-390 shortens the time of recovery from the neuroparalysis caused by traumatic or toxic degeneration of peripheral motor neurons. These syndromes are characterized by the activation of a proregenerative molecular axis, consisting of the CXCR4 receptor expressed at the damaged site in neuronal axons and by the release of its ligand CXCL12α, produced by surrounding Schwann cells. This intercellular signaling axis promotes axonal growth and functional recovery from paralysis. NUCC-390 is an agonist of CXCR4 acting similarly to CXCL12α. Here, we have tested its efficacy in a murine model of neuroparalytic envenoming by a Papuan Taipan (Oxyuranus scutellatus) where a degeneration of the motor axon terminals caused by the presynaptic PLA2 toxin Taipoxin, contained in the venom, occurs. Using imaging of the neuromuscular junction and electrophysiological analysis, we found that NUCC-390 administration after injection of either the purified neuroparalytic Taipoxin or the whole Taipan venom, significantly accelerates the recovery from paralysis. These results indicate that NUCC-390, which is non-toxic in mice, should be considered for trials in humans to test its efficacy in accelerating the recovery from the peripheral neuroparalysis induced by Taipans. NUCC-390 should be tested as well in the envenomation by other snakes that cause neuroparalytic syndromes in humans. NUCC-390 could become an additional treatment, common to many snake envenomings, that can be delivered after the bite to reduce death by respiratory deficits and to shorten and improve functional recovery.

An agonist of the CXCR4 receptor is therapeutic for the neuroparalysis induced by Bungarus snakes envenomingDear Editor, Here, we report the therapeutic properties of a small molecule agonist of the CXCR4 receptor on the recovery from the peripheral flaccid neuroparalysis caused by Bungarus snakebites. Snake envenoming is a neglected disease that, each year, causes >100 000 deaths in tropical and subtropical areas of the world and leaves >400 000 envenomed patients with permanent disabilities, with associated high social costs (https://www.who.int/news-room/ fact-sheets/detail/snakebite-envenoming). This is a disease of poverty believed by experts to be under reported. 1 Moreover, snake envenoming strikes particularly in lower income and rural parts of the world where advanced hospital care may not be rapidly available to the envenomed patient.A major number of neuropathological snakebites are produced by snakes of the Bungarus genus widely distributed in Asia. 2 Their venoms induce a descending flaccid paralysis with respiratory failure and autonomic dysfunctions. A large reduction of the function of the neuromuscular junction (NMJ) can be recorded electrophysiologically within few hours from snakebite, 2 and death may occur by respiratory failure. Mechanically ventilated patients survive because the Bungarus neurotoxins do not kill motor neurons but induce a rapid degeneration limited to the axon terminals which is followed by a slow regeneration requiring prolonged hospitalization (3-5 weeks) and eventual recovery. 2,3 However, hospitalization with mechanical ventilation poses major problems in lowincome countries associated with high costs and risks of in-hospital complications.The pathophysiology of Bungarus snake envenoming is primarily driven by neurotoxicity caused by protein neurotoxins. 2,3 The presynaptically acting βbungarotoxins (β-BTX) are phospholipases A 2 that cleave the ester bond of the fatty acid in the sn-2 site of the glycerol moiety of phospholipids, causing accumulation of fatty acids and lysophospholipids leading to rapid degeneration of axon terminals within few hours in mice. 4 This is fol-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Snake envenoming is a major but neglected human disease in tropical and subtropical regions. Among venomous snakes in the Americas, coral snakes of the genus Micrurus are particularly dangerous because they cause a peripheral neuroparalysis that can persist for many days or, in severe cases, progress to death. Ventilatory support and the use of snake species-specific antivenoms may prevent death from respiratory paralysis in most cases. However, there is a general consensus that additional and non-expensive treatments that can be delivered even long after the snake bite are needed. Neurotoxic degeneration of peripheral motor neurons activates pro-regenerative intercellular signaling programs, the greatest of which consist of the chemokine CXCL12α, produced by perisynaptic Schwann cells, which act on the CXCR4 receptor expressed on damaged neuronal axons. We recently found that the CXCR4 agonist NUCC-390 promotes axonal growth. Here, we show that the venom of the highly neurotoxic snake Micrurus nigrocinctus causes a complete degeneration of motor axon terminals of the soleus muscle, followed by functional regeneration whose time course is greatly accelerated by NUCC-390. These results suggest that NUCC-390 is a potential candidate for treating human patients envenomed by Micrurus nigrocinctus as well as other neurotoxic Micrurus spp. in order to improve the recovery of normal neuromuscular physiology, thus reducing the mortality and hospital costs of envenoming.